Cancer remains the second most common cause of death, accounting for nearly 1 out of every 4 deaths in the United States. It is estimated that more than 1.7 million new cases of cancer will be diagnosed in the United States in the year 2014 alone.
Aberrant epigenetic silencing of tumor suppressor genes is believed to result in tumorigenesis. Aberrant epigenetic silencing could occur as a result of changes in covalent modification of histone proteins. Enzymatic modifications such as acetylation, methylation, and phosphorylation of the lysine side chains in the N-terminus of histones regulate the access to DNA by transcriptional factors, thereby regulating gene expression. Histone acetylation is modulated by two protein families, histone acetyltransferases (HATs) and histone deacetylases (HDACs).
Histone deacetylases (HDACs) are a family of enzymes that catalyzes the de-acteylation of lysine amino acid side chains of histones in chromatin. HDACs remove the acetyl group from lysine residues of histone proteins to form a transcriptionally inactive condensed form of chromatin. This results in a closed, transcriptionally inactive chromatin state, which can result in silencing of tumor suppressor genes and promoting cancer initiation and/or progression. Thus, HDACs play an important role in gene expression. Inhibition of HDACs may be used to reactivate these undesirably silenced genes in the epigenetic regulation of gene expression without changing DNA sequences for developing anticancer agents.
HDAC proteins are a family of at least 18 enzymes classified into four groups based on their size, cellular localization, active catalytic site numbers, and homology to yeast HDAC proteins: class I includes HDAC 1, -2, -3, and -8; class IIa includes HDAC4, -5, -7, and -9; class IIb includes HDAC6 and -10; class III includes sirtuin proteins; and class IV includes HDAC11.
HDAC inhibitors reactivate silent tumor suppressor genes, resulting in cancer cell apoptosis. HDAC inhibitors block tumor cell proliferation by inducing cell differentiation, cell cycle arrest, and/or apoptosis, and these compounds make up some of the therapies currently approved or in clinical trials for cancer chemotherapy. Class I HDAC isoforms are regarded as promising cancer targets. Two HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA, Vorinostat), and FK228 (romidepsin), have been approved by the USFDA for the treatment of cutaneous T-cell lymphoma (CTCL). The compound SAHA, with a hydroxamic acid moiety as the metal binding domain, is a pan-inhibitor of HDACs, non-selective for all HDAC isoforms. FK228 is a class I selective inhibitor. The metal binding domain of FK228 is a thiol masked as a cyclic disulfide bond with a cysteine residue of the depsipeptide core. A number of other HDAC inhibitors are in different stages of clinical studies. However, there is a need for isoform-selective or class-selective inhibitors for higher therapeutic potential and reduced side effects. There is also a need for the development of more potent HDAC inhibitors, as well as HDAC inhibitors not prone to drug resistance. It would also be useful to synthesize selective HDAC inhibitors that are useful as probes to determine the physiological/pathogenic role of individual HDAC isoforms.